The present invention relates to pharmaceutical compositions used in the treatment of arthritic conditions, especially rheumatoid arthritis.
Rheumatic diseases are conditions in which pain and stiffness are prominent in portions of the musculoskeletal system, including the connective tissue. Arthritis is the general name used for such conditions when the joints, themselves, are the major seat of the rheumatic disease. Arthritis is one of the oldest known diseases. Chronic arthritis of the spine is known to have been present in the ape man of 2 million years ago, as well as in the Java and Lansing Men of 500 thousand years ago, and Egypian mummies dating to 8,000 B.C. See Osgood, R. B., Amer. J. Med. Sci., 200: 429(1940). The Romans built extensive baths throughout their empire to aid in the treatment of arthritic diseases. Yet, in spite of this long history, the search for a safe and effective therapy for arthritic conditions continues. The importance of such work is underscored by the fact that there are over 20 million persons in the United States, today, suffering from some form of arthritis or related disease. Further, arthritis and rheumatism result in 27 million lost work days yearly, second only to heart disease as a cause of chronic limitation of ability to work.
Various gold salts have been recognized as an effective therapy for the treatment of rheumatoid arthritis. See McCarty, D. J., Arthritis and Allied Conditions, Lea & Febiger, 1979, pages 355-364. Gold was originally used to treat rheumatoid arthritis in the 1920's; this use was based on the empirical belief that since gold was of value in the treatment of tuberculosis, a chronic form of infectious disease, it might be efficacious in yet another chronic disorder suspected, at the time, of having an infectious etiology. Early work in the treatment of arthritic conditions using gold (Chrysotherapy) is summarized in Forestier, J., J. Lab. Clin. Med., 20: 827(1935).
A major deterrent to the use of gold therapy is the frequent occurrence of side effects associated with such treatment; some tests indicate that 25 to 40 out of every 100 patients treated with gold salts will develop some degree of toxic reaction. One such side effect is renal toxicity, such as nephrosis. If renal toxicity side effects become apparent, it is necessary to discontinue the gold therapy and treat the side effect with corticosteroids. Thus, the occurrence of such side effects clearly curtails the usefulness of gold salt therapy in the treatment of arthritic conditions. Similar renal toxicity problems can occur where other metals are used to treat medical conditions, such as in the treatment of depression using lithium salts. From the foregoing, it is clear that it would be desirable to be able to formulate an effective treatment regimen for arthritic conditions, incorporating the use of gold salts, while minimizing the potential renal toxicity side effects of such treatment. Gold salt therapy also tends to inhibit bone mineralization; a treatment regimen which minimizes this effect would also be highly desirable. See Jessop, Gold In The Treatment of Rheumatoid Arthritis- Why, When and How?, J. Rheumatol. (Suppl. 5), 6: 12-17 (1979); Davis, Undesirable Effects of Gold Salts, J. Rheumatol. (Suppl. 5), 6: 18-24 (1979); and Martindale, The Extra Pharmacopoeia, 26th Edition, The Pharmaceutical Press, London, 1975, pages 477-479.
Organophosphonate compounds are reported in the literature as being useful in the treatment of anomalous mobilization and deposition of calcium phosphate salts (bone mineral) in humans and other animals; use of these compounds in the treatment of arthritis is specifically disclosed. See especially, U.S. Pat. Nos. 3,683,080, Francis, granted Aug. 8, 1972; 4,234,645, Gunther and Fleisch, issued Nov. 18, 1980; and 4,216,212, Flora and Francis, issued Aug. 5, 1980.
The article by Francis, Flora and King, entitled "The Effects of Disodium Ethane-1-Hydroxy-1,1-Diphosphonate on Adjuvant Induced Arthritis in Rats", appearing in Calc. Tiss. Res., 9: 109-121 (1972) discloses the use of a diphosphonate material in the treatment of arthritis in rats and mentions the use of phosphonates to inhibit inflammatory erosion in rat cartilage.
It is an object of the present invention to provide pharmaceutical compositions, comprising organophosphonates and gold salts, which are effective in the treatment of arthritic conditions while minimizing the renal toxicity and inhibition of bone mineralization which can accompany treatment with gold salts.
It is a further object of the present invention to provide a method for treating arthritic conditions utilizing combinations of organophosphonates and gold salts.